Chymase is one of the neutral proteases present in mast cell granules, and is deeply involved in a variety of biological processes in which mast cells participate. Various effects have been reported including, for example, the promotion of degranulation from mast cells, the activation of interleukin-1β (IL-1β), the activation of matrix protease, the decomposition of fibronectin and type IV collagen, the promotion of the release of transforming growth factor-β (TGF-β), the activation of substance P and vasoactive intestinal polypeptide (VIP), the conversion of angiotensin I (Ang I) to Ang II, the conversion of endothelin, and the like.
The above indicates that inhibitors of said chymase activity may be promising as preventive and/or therapeutic agents for diseases of respiratory organs such as bronchial asthma, inflammatory/allergic diseases, for example allergic rhinitis, atopic dermatitis, and urticaria; diseases of circulatory organs, for example. sclerosing vascular lesions, intravascular stenosis, disturbances of peripheral circulation, renal failure, and cardiac failure; diseases of bone/cartilage metabolism such as rheumatoid arthritis and osteoarthritis, and the like.
As inhibitors of chymase activity, there are known triazine derivatives (Japanese Unexamined Patent Publication (Kokai) No. 8-208654); hydantoin derivatives (Japanese Unexamined Patent Publication (Kokai) No. 9-31061); imidazolidine derivatives (PCT Application WO 96/04248); quinazoline derivatives (PCT Application Wo 97/11941); heterocyclic amide derivatives (PCT Application WO 96/33974); and the like. However, the structures of these compounds are entirely different from those of the compounds of the present invention.
On the other hand, an art related to the compounds of the present invention is disclosed in U.S. Pat. No. 5,124,336. Said specification describes thiobenzimidazole derivatives as having an activity of antagonizing thromboxane receptor. The specification, however, makes no mention of the activity of said compounds to inhibit human chymase.
Thus, it is an object of the present invention to provide novel compounds that are potential and clinically applicable inhibitors of human chymase.